Erectile dysfunction is the inability to obtain and maintain a penile erection sufficient for sexual intercourse or other sexual expression. A number of factors can place an individual at risk for this disorder, for example, trauma, pelvic surgery, hypercholesterolemia, ischemic heart disease, peripheral vascular disease, chronic renal failure, diabetes, or the use of medicaments such as certain antihypertensive medications or digoxin, or illicit drugs, cigarettes or alcohol. Methods for the treatment of erectile dysfunction include the use of vacuum devices and penile implants, as well as the administration of medicaments such as yohimbine, papaverine and apomorphine. Improved methods for the treatment of this disorder are sought, however, as the aforementioned methods do not provide sufficient efficacy, and/or are accompanied by drawbacks or side effects such as erosion, pain, priapism or gastrointestinal discomfort.
As penile erection is dependent upon the presence of adequate levels of cyclic guanosine 3', 5'-monophosphate (cGMP), especially in corpora cavernosa tissue, administration of an inhibitor of a cGMP phosphodiesterase (cGMP PDE) (and particularly, a selective inhibitor of cGMP PDE Type V (cGMP PDE V)) provides a means for achieving and maintaining an erection, and therefore for treating erectile dysfunction. See Trigo-Rocha et al., "Nitric Oxide and cGMP: mediators of pelvic nerve-stimulated erection in dogs," Am. J. Physiol., Vol. 264 (February 1993); Bowman et al., "Cyclic GMP mediates neurogenic relaxation in the bovine retractor-penis muscle," Br. J. Pharmac., 81, 665-674 (1984); and Rajfer et al., "Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission," New England J. Med., 326, 2, 90-94 (January 1992). Sildenafil, for example, has been described as a phosphodiesterase Type V inhibitor useful for the treatment of erectile dysfunction. See Drugs of the Future, 22, 138-143 (1997).
The present invention provides novel compounds which are potent and selective inhibitors of cGMP PDE V which may be employed in the treatment of erectile dysfunction. In view of their activity, the present compounds can also be employed in the treatment of other disorders responding to the inhibition of cGMP PDE such as various cardiovascular disorders.